Bone Metastasis Treatment with Bisphosphonates

Julia Draznin Maltzman, MD and Modified by Lara Bonner Millar, MD The Abramson Cancer Center of the University of Pennsylvania Last Modified: December 18, 2014

Introduction

Bone metastases are a common complication of advanced cancer. They are especially prevalent (up to 70%) in breast and prostate cancer. Bone metastases can cause severe pain, bone fractures, life-threatening electrolyte imbalances, and nerve compression syndromes. The pain and neurologic dysfunction may be difficult to treat and significantly compromises the patients' quality of life. Bone metastases usually signify advanced, often incurable disease.

Osteolytic vs. osteoblastic

Bony metastases are characterized as being either osteolytic or osteoblastic. Osteolytic means that the tumor caused bone break down or dissolution. This usually results in loss of calcium from bone. On X-rays these are seen as holes called "lucencies" within the bone. Diffuse osteolytic lesions are most characteristic of a blood cancer called Multiple Myeloma, however they may be present in patients with many other types of cancer.

Osteoblastic bony lesions, by contrast, are characterized by increased bone production. The tumor somehow signals to the bone to overproduce bone cells and result in rigid, inflexible bone formation. The cancer that typically causes osteoblastic bony lesions is prostate cancer. Most cancers result in either osteolytic or osteoblastic bony changes, but some malignancies can lead to both. Breast cancer patients usually develop osteolytic lesions, although at least 15-20 percent can have osteoblastic pathology.

Why the bone?

The bone is a common site of metastasis for many solid tissue cancers including prostate, breast, lung, kidney, stomach, bladder, uterus, thyroid, colon and rectum. Researchers speculate that this may be due to the high blood flow to the bone and bone marrow. Once cancer cells gain access to the blood vessels, they can travel all over the body and usually go where there is the highest flow of blood. Furthermore, tumor cells themselves secrete adhesive molecules that can bind to the bone marrow and bone matrix. This molecular interaction can cause the tumor to signal for increased bone destruction and enhance tumor growth within the bone. A recent scientific discovery showed that the bone is actually a rich source of growth factors. These growth factors signal cells to divide, grow, and mature. As the cancer attacks the bone, these growth factors are released and serve to further stimulate the tumor cells to grow. This results in a self-generating growth loop.

What are the symptoms of bone metastasis?

It must be recognized that the symptoms of bone metastasis can mimic many other disease conditions. Most people with bony pain do not have bone metastasis. That being noted, the most common symptom of a metastasis to the bone is pain. Another common presentation is a bone fracture without any history of trauma. Fracture is more common in lytic metastases than blastic metastases.

Some people with more advanced disease may come to medical attention because of numbness and tingling sensation in their feet and legs. They may have bowel and bladder dysfunction – either losing continence to urine and/or stool, or severe constipation and urinary retention. Others may complain of leg weakness and difficulty moving their legs against gravity. This would imply that there is tumor impinging on the spinal cord and compromising the nerves. This is considered an emergency called spinal cord compression, and requires immediate medical attention. Another less common presentation of metastatic disease to the bone is high levels of calcium in the body. High calcium can make patients constipated, result in abdominal pain, and at very high levels, can lead to confusion and mental status changes.

Diagnosis of bone metastasis

Once a patient experiences any of the symptoms of bone metastasis, various tests can be done to find the true cause. In some cases bone metastasis can be detected before the symptoms arise. X-rays, bone scans, and MRIs are used to diagnose this complication of cancer. X-rays are especially helpful in finding osteolytic lesions. These often appear as "holes" or dark spots in the bone on the x-ray film. Unfortunately, bone metastases often do not show up on plain x-rays until they are quite advanced. By contrast, a bone scan can detect very early bone metastases. This test is done by injecting the patient with a small amount of radio-tracing material in the vein. Special x-rays are taken sometime after the injection. The radiotracer will preferentially go to the site of disease and will appear as a darker, denser, area on the film. Because this technique is so sensitive, sometimes infections, arthritis, and old fractures can appear as dark spots on the bone scan and may be difficult to differentiate from a true cancer. Bone scans are also used to follow patients with known bone metastasis. Sometimes CT scan images can show if a cancer has spread to the bone. An MRI is most useful when examining nerve roots suspected of being compressed by tumor or bone fragments due to tumor destruction. It is used most often in the setting of spinal cord compromise.

There are no real blood tests that are currently used to diagnose a bone metastasis. There are, however, a number of blood tests that a provider can obtain that may suggest the presence of bone lesions, but the diagnosis rests with the combination of radiographic evidence, clinical picture, and natural history of the malignancy. For example, elevated levels of calcium or an enzyme called alkaline phosphatase can be related to bone metastasis, but these lab tests alone are insufficient to prove their presence.

Treatment

The best treatment for bony metastasis is the treatment of the primary cancer. Therapies may include chemotherapy, hormone therapy, radiation therapy, immunotherapy, or treatment with monoclonal antibodies. Pain is often treated with narcotics and other pain medications, such as non-steroidal anti-inflammatory agents. Physical therapy may be helpful and surgery may have an important role if the cancer resulted in a fracture of the bone.

Bisphosphonates

Bisphosphonates are s category of medications that decrease pain from bone metastasis and may improve overall bone health. Bisphosphonates man-made versions of a naturally occurring compound called pyrophosphate that prevents bone breakdown. They are a class of medications widely used in the treatment and prevention of osteoporosis and certain other bone diseases (such as Paget's Disease), as well as in the treatment of elevated blood calcium. These drugs suppress bone breakdown by cells called osteoclasts, and, can indirectly stimulate the bone forming cells called osteoblasts. It is for this reason, and for the fact that bisphosphonates are very effective in relieving bone pain associated with metastatic disease, that they have transitioned to the oncology arena. However, treatment of bone metastases is not curative. There is increasing evidence that bisphosphonates can prevent bony complications in some metastatic cancers and may even improve survival in some cancers. Most researchers agree that these drugs are more helpful in osteolytic lesions and less so in osteoblastic metastasis in terms of bone restoration and health, but the bisphosphonates are able to alleviate pain associated with both types of lesions. The appropriate time to start treatment is once a bone metastasis has been identified on imaging.

Bisphosphonates can be given either orally or intravenously. The latter is the preferred route of administration for many oncologists as it is given monthly as a short infusion and does not have the gastrointestinal side effects that the oral bisphosphonates have. There are currently two approved and commonly used IV bisphosphonates –Pamidronate disodium (Aredia, Novartis) and zolendronic acid (Zometa, Novartis). Their side effect profile is fairly mild and includes a flu-like reaction during the first 48 hours after the infusion, kidney impairment and osteonecrosis of the jaw with long term use. Patients with renal impairment may not be candidates for this therapy.

Bisphophonates may have some level of anti-tumor activity in breast cancer. A recent Phase III clinical trial revealed that the addition of Zometa to endocrine therapy, improves disease-free survival, but not overall survival, in pre-menopausal patients with estrogen-receptor postive early breast cancer. Another trial called AZURE found no effect from the bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, several other studies on bisphosphonates and breast cancer are ongoing, and for now, their use is not recommended in patients without metastases.

In addition to bisphosphonates, osteoclast inhibition can also be achieved through other means. Another medication, Denosumab (XGEVA, Amgen), targets a receptor called receptor activator of nuclear factor kappa B ligand (RANKL), is able to block osteoclast formation. A few studies comparing Denosumab to bisphosphonates have found Denosumab results in a longer time to skeletal events, on the order of a few months, compared to bisphosphonates, however many experts believe that the evidence is not strong enough to support one class of drug over another. The most common side effects of Denosumab are fatigue or asthenia, hypophosphatemia, hypocalcemia and nausea. Patients receiving bisphosphonates or denosumab should also be taking calcium and vitamin D supplementation.

The future

Skeletal metastases remain one of the more debilitating problems for cancer patients. Research is ongoing to identify the molecular mechanisms that result in both osteolytic and osteoblastic bone lesions. Perhaps the use of proteomics and gene array data may permit us to identify some factors specific to the tumor or to the bony lesion itself that could be used as therapeutic targets to teat or even prevent this complication.